Chapter 55 Painful Peripheral Neuropathies Flashcards
KEY POINTS 1. Neuropathic pain arises from disorders of the peripheral nervous system. Although there are many etiologies of peripheral neuropathy, not all of which always produce pain, the most prominent and common is diabetic neuropathy. 2. Many mechanisms have been proposed for the pain that occurs in peripheral neuropathic states. They can be categorized into peripheral and central. Peripheral mechanisms proposed include: formation of ectopic foci, formation of ephapses (unlikely), rele
Neuropathy
a general term used to describe disease of
nerve function and structures
Neuropathies arise from
many different etiologies
diabetic peripheral neuropathy, postherpetic neuropathy, chemotherapy-induced
peripheral neuropathy, HIV neuropathy, and neuropathy of chronic renal failure) and can be painful or painless. They can affect the central nervous system (CNS), the
peripheral nervous system, or both simultaneously.
Neuropathies result from
physical injury, inherited genetic disorders, infection, autoimmune disorders, and most often systemic disease.
mononeuropathy
polyneuropathy
Neuropathies can affect solely one single nerve, termed a mononeuropathy, or several separate
nerves, which is termed a polyneuropathy.
nociceptive pain
Pain is considered a normal, adaptive, or physiologic response when it results from nociceptors (pain receptors) having been activated by tissue disease or damage
neuropathic pain arises
from
spontaneous activity within the nervous system, or
an aberrant response to “normal” sensory stimulation (e.g., fine touch evoking pain).
Mononeuropathy multiplex
reflects changes
in multiple single, discreet nerves.
Polyneuropathy
reflects changes in sensation in a diffuse, often bilateral, pattern
that is not restricted to discreet nerves
Neuritis
a subtype
of neuropathy reserved for an inflammatory process
affecting the nerves.
Neuropathic pain
defined as pain initiated or
caused by a primary lesion or dysfunction in the nervous system has been revised to now include “pain arising as direct consequence of a lesion or disease affecting the
somatosensory system
Neuropathic pain can result from multiple causes and it can be categorized according to the site of initial injury
(central nervous system, peripheral nervous system, or mixed) and
the condition causing disease.
Paresthesias
Abnormal nonpainful sensations that may be spontaneous or evoked (tingling or “pins and needles” sensations
Dysesthesias
Abnormal pain that may be spontaneous or evoked
unpleasant tingling
Hyperpathia
An exaggerated painful response evoked by a noxious or
non-noxious stimulus
Allodynia
A painful response to a normally non-noxious stimulus
e.g., light touch is perceived as burning pain
Hyperalgesia
An exaggerated painful response to a normally noxious stimulus
Spontaneous pain
Painful sensation with no apparent external
stimulation
mechanisms are thought to be responsible for the
development of neuropathic pain
These include changes
in ion channel number and density resulting in central and peripheral sensitization. Other changes include cortical
reorganization and disinhibition of neuronal circuitry, and cellular and molecular changes as a result of the immune
response following the initial nerve damage. The sympathetic nervous system is also thought to play a role in maintaining neuropathic pain
Following trauma to a nerve, sodium channels
accumulate in a higher than normal concentration around the area of injury and along the entire axon, resulting in hypersensitivity
of the nerve and ectopic foci
nerve injury can result in the release of
neuropeptides that might further cause peripheral sensitization through neurogenic inflammation. Nerve injury also can result in sprouting of sympathetic fibers into the dorsal root ganglia of the affected nerve.
The CNS undergoes changes with peripheral nerve injury.
peripheral neuropathy results in reduced input to the CNS (postherpetic neuralgia, diabetic neuropathy).
In diabetic neuropathy, there is little evidence
that peripheral sensitization
as might be seen with
increased sodium channels or with ephaptic transmission) occurs; rather the evidence points toward reduced neural input to the CNS.
potential mechanisms exist for a central contribution to the pain from peripheral neuropathy
Loss of large fiber (A-b) sensory input could result in a reduction in non-nociceptive sensory input, thereby reducing the effectiveness of the “gate.” opioid and GABA receptors (both involved in inhibition of nociceptive transmission in the CNS) are down regulated and the amount of GABA in the dorsal horn is reduced. death of dorsal horn interneurons in lamina II (many of which
are involved in inhibition of nociceptive transmission in the dorsal horn) by overexposure to excitatory amino acids. Cholecystokinin, involved in opioid receptor inhibition, has also been found to be upregulated in the spinal cord following experimental nerve injury
Common Conditions Causing Neuropathic Pain Syndromes
Physical Injury/Trauma
Complex regional pain syndrome (CRPS), Type I & II Radiculopathy
Stroke (cerebrovascular accident)
Spinal cord injury
Common Conditions Causing Neuropathic Pain Syndromes
Inherited/Genetic
Charcot-Marie-Tooth
Fabry’s disease
Common Conditions Causing Neuropathic Pain Syndromes
Infections/Autoimmune
Human immunodeficiency virus
Herpes simplex virus
Acute inflammatory demyelinating polyneuropathy
Common Conditions Causing Neuropathic Pain Syndromes
Systemic Disease
Diabetes mellitus
Kidney disorders/renal failure
Vitamin deficiencies (beriberi, alcoholic pellagra,
vitamin B12 deficiency)
Vascular disorders
Chemical toxins (isoniazid, chemotherapy agents)
(platinum, vinca alkaloids, taxanes), arsenic, thallium
Hypothyroidism
Amyloidosis
Multiple myeloma
A central mechanism that may explain the allodynia seen
in some peripheral neuropathies involves
A-b fiber sprouting and A-b fiber “phenotypic switching.” A-b fibers
normally synapse in all lamina of the spinal cord except lamina II, where C-fiber input predominates. However, following peripheral C-fiber nerve injury, A-b fiber “sprouting” into lamina II occurs, therefore allowing mechanical non-nociceptive input via the peripheral A-b fibers to trigger second-order pain pathways.
A-b fibers in the dorsal horn do not normally express substance P (as seen in C-fibers), but following peripheral nerve injury
they can (phenotypic switching). When this happens, they thereby allow non-nociceptive input to trigger CNS nociceptive transmission.
patient presents with signs and symptoms suggestive of neuropathic pain
allodynia, hypoand/
or hyper-algesia, and paresthesias
Focal lesions of peripheral nerves (mononeuropathies) result frequently from
processes that produce localized damage
and include nerve entrapment; mechanical injuries; thermal, electrical, or radiation injuries; vascular lesions; and neoplastic or infectious processes
polyneuropathies often result in
a bilateral and symmetric disturbance in function as a result of agents that act diffusely on the peripheral nervous system: toxic substances, deficiency states, metabolic disorders, and immune reactions
the most important pieces of historical information
The location of the pain and other symptoms
In the patient suspected of having polyneuropathy, the clinician should focus on
sensory evaluation. Strength and deep tendon reflexes are preserved in many patients with
polyneuropathy. In addition to testing vibration, proprioception,
and light touch, the sensory examination should include several special stimuli including light-touch rubbing, ice, single pinprick, and multiple pinpricks.
sensory evaluation
Lightly stroking the affected area with a finger will assess for allodynia (pain provoked by non-noxious stimuli). Ice
application will test for both temperature sensation and abnormal sensations such as pain and lingering after sensations. Single pinprick testing may elicit a sensory
deficit or hyperpathia. Repeated pinprick testing may elicit summation (pain growing more intense with subsequent stimuli) or lingering after sensations, both common findings in polyneuropathy
Patients suspected of having polyneuropathy can be considered
for what ELECTRODIAGNOSTIC TESTING
electromyography (EMG) and nerve conduction velocity (NCV) studies, which may offer insights into whether the process is a demyelinating (reductions in nerve conduction velocities) or axonal (reductions in the
amplitude of evoked responses) neuropathy.
Quantitative sensory testing (QST) may be the most useful in
the assessment and longitudinal monitoring of painful peripheral neuropathies. While large fibers are assessed through the use of sensory thresholds to vibration, small fibers can be assessed by
threshold for detection of heat, painful heat, cold, and painful cold stimuli.
cause of diabetic neuropathy
has not been determined
with certainty. Current hypotheses focus on the
possibilities of metabolic and ischemic nerve injury.
Pathologic examination of nerves taken from diabetic
patients has shown evidence of microvascular disease supporting
the ischemic nerve theory
Metabolic abnormalities of diabetic neuropathy
include
(1) accumulation of sorbitol in diabetic nerve as excess glucose is converted to sorbitol by the enzyme
aldose-reductase,
(2) autooxidation of glucose resulting in
reactive oxygen molecules, and
(3) inappropriate activation
of protein kinase C.
Diabetic neuropathy can be divided by the pattern of distribution of involved nerves
Mononeuropathy
- Cranial mononeuropathy
- Compression mononeuropathy
Mononeuropathy multiplex - Proximal motor neuropathy
- Truncal neuropathy
Polyneuropathy
- Distal symmetric polyneuropathy
- Painful diabetic neuropathy
- Autonomic polyneuropathy
distal symmetric
polyneuropathy
most common form of diabetic neuropathy. It is predominantly a sensory disturbance. Patients often present with gradual onset of paresthesias
and pain in the legs and feet. Symptoms begin in the toes and gradually ascend over months to years to involve more
proximal levels. The fingertips and hands become involved later, usually when symptoms in the lower extremities have ascended to the knee level. Allodynia and burning pain are common and are often worse
at night.
in Diabetic neuropathy
distal symmetric
polyneuropathy
Examination shows
graded distal sensory loss
predominantly affecting vibration and position sensation. Reflexes may be diminished or absent.
in Diabetic neuropathy
distal symmetric
Electrophysiologic testing shows
a decrease in the amplitude of evoked
responses to a greater degree than reduction in nerve conduction velocities as the neuropathy progresses. This reflects primarily axonal damage rather than demyelination
Severe sensory loss may allow repeated trauma to go unnoticed, resulting in
development of foot ulcers and diabetic
neuroarthropathy (Charcot’s joints)
syndrome of acute painful diabetic neuropathy
characterized by the rapid onset of severe pain in the distal lower extremities characterized by constant burning in the feet, dysesthesia, allodynia, and lancinating leg pains.
In syndrome of acute painful diabetic neuropathy Examination shows
little or no sensory loss with preserved reflexes. Electrophysiologic testing shows decreased amplitude or absent sensory potentials, but may also be normal. This type of neuropathy often remits within a year after blood sugars are controlled
Autonomic neuropathy
Symptomatic autonomic neuropathy most often occurs as a component of distal symmetric polyneuropathy. Autonomic nervous system abnormalities include postural hypotension, impaired heart rate control (resting
tachycardia and fixed heart rate), esophageal dysmotility, gastroparesis, and erectile dysfunction.
Lower extremity proximal motor neuropathy
an uncommon painful disorder associated with diabetes. It is characterized by acute or subacute onset of moderate to marked weakness and wasting of the pelvifemoral muscles
accompanied by back, hip, and thigh pain with preserved sensation in the regions of pain. The condition may be
painless or accompanied by pain described as a constant, severe, deep ache.
Diabetic lumbosacral radiculoplexus neuropathy (DLRPN)
referred to as diabetic amyotrophy, proximal
diabetic neuropathy, diabetic polyradiculopathy, Bruns- Garland syndrome, or diabetic lumbar plexopathy. It usually affects individuals with diabetes mellitus Type II
over the age of 50 years, and presents as an asymmetric weakness associated with pain in the legs that appears subacutely and progresses over weeks to months. Although motor function recovery is slow and often incomplete, the
pain usually resolves.
Diabetic truncal neuropathy involves
acute or gradual
onset of unilateral pain in the chest or abdomen and may mimic myocardial infarction, intra-abdominal pathology, or spinal disorders. Examination shows marked allodynia
and hyperpathia in the distribution of pain. EMG typically demonstrates denervation in the abdominal or intercostal musculature
Cranial mononeuropathies
involving the oculomotor,
abducens, trochlear, and facial nerves may occur in diabetic patients. The most common of these is oculomotor neuropathy that is manifest as ophthalmoplegia and ptosis. The eye is deviated laterally and has impaired movement
vertically and medially
Entrapment neuropathies are believed to occur more frequently in patients with diabetes mellitus
Carpal tunnel syndrome is believed to occur more than twice as frequently as in the nondiabetic population.
Amyloidosis
a disease caused by extracellular deposition of amyloid, a fibrous protein. Amyloidosis can be primary, familial, or
associated with other conditions such as multiple myeloma,
chronic infectious or inflammatory states, aging, and longterm hemodialysis.
characterize painful peripheral neuropathy in amyloidosis.
Deep aching and occasional shooting pains, distal sensory
loss, and autonomic and motor involvement
Treatment of
neuropathy associated with amyloidosis is aimed at
the underlying condition when such is identifiable
Multiple myeloma
due to malignant plasma cell growth. Painful neuropathy can appear in myeloma with or without
amyloid deposition. The neuropathy is extremely variable in severity and rate of progression, ranging from a mild, predominantly sensory neuropathy to a complete tetraplegia. Pain in myeloma often declines with successful treatment
using chemotherapy, radiation therapy (especially for isolated
plasmocytomas), or plasmapheresis.
untreated hypothyroidism may develop painful sensorimotor neuropathy
present with longstanding pain in either the hands
or the feet accompanied by weakness in the distal limb musculature.
The neuropathy often resolves with successful
replacement of thyroid hormone.
Thiamine deficiency seen in
alcoholics, chronic dialysis
patients, and people on restrictive diets
Thiamine deficiency
lead to beriberi
consists of heart failure, vasodilatation, and peripheral neuropathy. Hand foot, and calf pains with allodynia, decreased sensation, and motor involvement characterize the neuropathy.
Alcoholic neuropathy is characterized by
motor and sensory deficits, often accompanied by pain.
The pain consists of aching in the legs or feet with intermittent
lancinating pains. The upper limbs are rarely
involved. Burning of the soles and allodynia may also occur.
Alcoholic neuropathy occurs only after
chronic and severe alcohol abuse and is invariably accompanied
by severe nutritional deficiency. Treatment
consists of abstinence and thiamine supplementation.
Pellagra
caused by niacin deficiency and is rarely
seen in developed countries. Signs and symptoms include dermatitis, gastrointestinal complaints, neurasthenia, and spinal cord dysfunction. Pellagra is associated with a mixed, painful polyneuropathy similar to that seen with
beriberi.
In Pellagra a predominant feature of the sensorimotor neuropathy
is
spontaneous pain in the feet and lower legs,
with tenderness of the calf muscles and cutaneous hyperesthesia
of the feet
Treatment of pellagra
with niacin often results in resolution of all symptoms except the peripheral neuropathy.
Isoniazid
is a frequently used antituberculous drug.
Chronic administration in individuals with slow metabolism of the drug (slow acetylators) is associated with the
development of painful neuropathy.
Isoniazid neuropathy Initial symptoms
distal numbness and tingling paresthesias are later accompanied by pain, which may be felt as a deep ache or burning.
The calf muscles are painful and tender, and walking often aggravates symptoms. Symptoms may be particularly
troublesome at night.
Isoniazid neuropathy treatment
Prophylactic coadministration of
pyridoxine (vitamin B6) prevents development of neuropathy; however, it is not therapeutic once the neuropathy develops
most common neurologic complication of cancer treatment is
chemotherapy-induced peripheral neuropathy
(CIPN), a common adverse effect of treatment with
platinum-derived, taxane, and vinca alkaloid chemotherapeutic
compounds. These chemotherapeutic agents exert their cytotoxic effect by binding to DNA and producing interstrand and intrastrand cross-linkage,
thus impairing DNA synthesis and transcription.
The development
of CIPN is the most common reason a
platinum- based chemotherapy regimen is changed to another agent, administered at a lower dose, or given in fewer or
less frequent cycles of therapy.
chemotherapy-induced peripheral neuropathy
(CIPN) earliest manifestations of neuropathy
decreased vibration
sense in the toes and loss of ankle jerk reflexes. At larger doses, paresthesias may appear and progress to severe dysesthesias. The neuropathy is reversible, but recovery may take more than a year after discontinuation of the agent.
Charcot-Marie-Tooth (CMT) disorders are subdivided into
demyelinating and
axonal forms, depending on EMG conduction studies
Most common symptoms in Charcot-Marie-Tooth
include lower extremity motor symptoms (foot deformity, difficulty ambulating), hyporeflexia, and sensory loss.
infectious neuropathies are very common
Mycobacterium leprae, although quite uncommon
in North America and Europe, is among the leading cause. It usually affects the skin and nerves, but there also exists a pure neural leprosy in about 4% to 10%40 of all leprosy
cases. Symptoms are found primarily in the form of mononeuritis
or mononeuritis multiplex.
The sensory neuropathies associated with HIV (HIV-SN) include
distal sensory polyneuropathy
(DSP) due to the viral infection and antiretroviral toxic neuropathy (ATN) due to the medical treatment of
the viral illness.
The onset of DSP can occur in either
the subacute or chronic phases, or following the
development of an AIDS-defining illness
The clinical
manifestation of antiretroviral toxic neuropathy (ATN)
can appear within the first week to 6 months of the initiation of antiretroviral therapy and may subside after its cessation. The painful peripheral
neuropathy results from both direct neuronal inflammatory injury to the nerve itself (DSP) and the treatment using HAARTs leading to mitochondrial dysfunction
The clinical features of HIV-SN
are dominated by painful
dysesthesia, allodynia, and hyperalgesia. Onset is
often gradual and most commonly begins with bilateral lower extremity involvement. The neuropathy progresses
in a length-dependent fashion with a worsening
gradient of disease from distal structures to those more proximal.
HIV-SN symptoms
The dysesthesias commonly first involve
the soles of the feet and progress proximally; when the symptoms encompass the dermatomes of the knee the patient will often report finger involvement. The first symptoms noted are often numbness or burning sensation following a diurnal cycle with the pain worse
at night. Shortly thereafter, patients will report allodynia and hyperalgesia of the involved structures.
In HIV- SN, as a result, wearing shoes and walking become
painful and the patient’s
gait becomes antalgic.
In HIV- SN motor involvement
There is minimal subjective or objective motor involvement and it is generally limited to the intrinsic muscles of the foot. Physical examination
shows a diminution or loss of ankle reflexes in
addition to the sensory findings.
Reactivation of a latent infection of varicella zoster virus (human herpes virus-3) in the trigeminal ganglia or the dorsal root ganglia can result in
facial or peripheral pain in
the dermatomal distribution of the affected nerves. The resulting condition herpes zoster or “shingles” can be
excruciatingly painful and can result in a chronic pain condition called postherpetic neuralgia (PHN).
risk factors for the
development of PHN.
Advanced age, greater severity of the rash, and presence and severity of a painful prodrome preceding the rash
clinical presentation of PHN
common in the thoracolumbar region, following a single or multiple dermatomes with a prodromal period followed by the eruption of a maculopapular vesicular rash. The pain is most often described as burning, stabbing, and/or
throbbing and is commonly associated with cutaneous allodynia of the region.
Prevention of PHN
in patients who had a herpes zoster reactivation was successful in those
who received acyclovir
Acute inflammatory demyelinating polyradiculoneuropathy
(AIDP) caused by Guillain-Barré syndrome (GBS) is
characterized by
areflexic and ascending motor paralysis with sensory paresthesias. It is often preceded by an infection, generally an upper respiratory tract infection or gastroenteritis.
Most frequently, if an agent is identified, EBV,
CMV, Mycoplasma pneumoniae, and Campylobacter jejuni are found
Guillain-Barré syndrome (GBS) symptoms
The onset of symptoms develops over several days, or more frequently, weeks. Pain is a common early symptom; weakness, usually in the legs, may progress to respiratory failure requiring mechanical ventilation. Sensory symptoms include paresthesias often
in the presence of decreased sensation in a glove-stocking
distribution. Autonomic dysfunction is also commonly evidenced by tachycardia and orthostatic hypotension.
Guillain-Barré syndrome (GBS) pain
The pain is principally
an ache, strain, or deep burning sensation in the
thigh or buttocks and can be quite severe. While pain in AIDP may be severe, it is usually transient. Pain is usually worse at night.
Guillain-Barré syndrome (GBS) diagnosis and treatment
Nerve conduction studies and lumbar puncture aid the diagnosis. General therapy for AIDP (Acute inflammatory demyelinating polyradiculoneuropathy) is supportive along with plasmapheresis and IVIG. Glucocorticoids and other immunosuppressants have not been clearly shown to be helpful.
IDIOPATHIC SMALL-FIBER NEUROPATHY
This condition usually presents with painful feet in patients over age 60. It can be defined as the presence of paresthesias (usually painful) with the
absence of significant large-fiber dysfunction (atrophy, loss of vibratory sense, or loss of reflexes). Diagnosis is often confirmed through tests of autonomic function, quantitative sensory testing, or skin biopsy
antidepressants treatment of peripheral neuropathic pain
TCAs (amitriptyline, nortriptyline, desipramine,
imipramine) are the best studied and most efficacious, followed
by SNRIs (duloxetine, venlafaxine) and then SSRIs (citalopram, paroxetine).
The side effect profile of the TCAs, primarily anticholinergic effects, limits their widespread
application, especially in patients with
autonomic neuropathy, glaucoma, cardiac arrhythmias, and urinary
hesitation.
Anticonvulsants are used very frequently and successfully
gabapentin and pregabalin, structural
analogs to (GABA), are considered first-line agents and are used in the treatment of a
multitude of neuropathic pain syndromes including radiculopathy,
CRPS Type I and II, diabetic neuropathy, postherpetic
neuralgia, and mixed neuropathic pain conditions.
Anticonvulsants side effects
sedation, dizziness, GI complaints, and lower extremity edema
Other antiepileptics shown to bring symptomatic relief
such as in
HIV neuropathy (lamotrigine), painful diabetic neuropathy (lacosamide), and postherpetic neuralgia (valproic acid)
Other oral medications that have shown beneficial effects but are generally employed in refractory cases or as second-line agents, include
opioids such as morphine or tramadol
treatment options that
have shown improvement in neuropathic pain include topical agents such as
lidocaine patches (postherpetic neuralgia,
post-traumatic neuralgia) or in experimental studies,
high-concentration (8%) capsaicin creams (HIV neuropathy, postherpetic neuralgia
treatment of patient without significant relief of their neuropathic
pain.
In these circumstances, various alternative options exist, including sympathetic nerve blocks, neurolytic sympathetic blocks, spinal cord stimulation (SCS), deep brain stimulation (DBS), transcutaneous electrical nerve stimulation (TENS), and repetitive transcranial magnetic stimulation (rTMS).
The use of spinal cord stimulation is well established in
neuropathic pain
conditions including postlaminectomy syndrome, CRPS
Type I, and diabetic peripheral neuropathy
Gabapentin
Start Dose:100–300 mg/day Maximum Dose: 3600 mg/day Documented Effect: PHN, PDN, HIV, mixed neuropathic pain Side Effects: Sedation, dizziness, edema
Pregabalin
Start Dose: 50–150 mg/day Maximum Dose: 300 mg/day, (600 mg/day fibromyalgia) Documented Effect: PHN, PDN, mixed neuropathic pain, fibromyalgia, central pain Side Effects: Sedation, dizziness, edema
Tricyclic
antidepressants (Nortriptyline, Desipramine
Trazadone)
Start Dose: 10–25 mg/day Maximum Dose: 50–150 mg/day Documented Effect: PHN, PDN, central pain, mixed neuropathic pain Side Effects: Cardiac, anticholinergic, sedation
Specific serotonergic
and noradrenergic
reuptake inhibitors (Venlafaxine, Duloxetine)
Start Dose: 37.5 mg/day 20 mg/day Maximum Dose: 25–375 mg/day, 60 mg/day Documented Effect: PHN, PDN, fibromyalgia Side Effects: Sedation
Carbamazepine
Start Dose: 300 mg/day Maximum Dose: 1200–1800 mg (1/3 higher dose for oxcarbazepine) Documented Effect: Trigeminal neuralgia Side Effects: Sedation, dizziness, ataxia, blood dyscrasias
Tramadol
Start Dose: 50–150 mg/day
Maximum Dose: 400 mg/day
Documented Effect: PHN, PDN
Side Effects: Sedation, dizziness, seizure
Lamotrigine
Start Dose: 25 mg/day Maximum Dose: 400–600 mg/day Documented Effect: Trigeminal neuralgia, poststroke central pain, HIV Side Effects: Sedation, tremor, rash
Opioids
Start Dose: 5–10 mg/day; titrate and substitute with
long-acting opioids
Maximum Dose: Variable, 100–200 mg (OME)/day
Documented Effect: PHN, PDN, post–amputation
pain
Side Effects: Sedation, dizziness, tolerance, drug abuse, misuse
Lidocaine patch
Start Dose: 5%
Maximum Dose: 3 patches/day
Documented Effect: PHN, traumatic nerve injury
Side Effects: Allergic reaction
Capsaicin cream
Start Dose: 0.025% and 0.075%
Maximum Dose: N/A
Documented Effect: PHN, PDN, HIV
